3-Phenyl-2-arylalkylthiopropionic acid derivatives as selective agonists of ppar-alpha

ABSTRACT

A compound of formula I 
                         
wherein R 1  represents chloro, fluoro or hydroxy as well as optical isomers and racemates thereof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, processes for preparing such compounds, their utility in treating clinical conditions associated with insulin resistance, methods for their therapeutic use and pharmaceutical compositions containing them.

This application is a national stage filing under 35 U.S.C. § 371 ofPCT/GB02/05743, filed Dec. 18, 2002 and claims foreign priority fromSweden patent application no. 0104333-0, filed Dec. 19, 2001.

FIELD OF THE INVENTION

The present invention relates to certain novel3-phenyl-2-arylalkylthiopropionic acid derivatives, to processes forpreparing such compounds, to their the utility in treating clinicalconditions including lipid disorders (dyslipidemias) whether or notassociated with insulin resistance and other manifestations of themetabolic syndrome, to methods for their therapeutic use and topharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The metabolic syndrome including type 2 diabetes mellitus, refers to acluster of manifestations including insulin resistance with accompanyinghyperinsulinaemia, possibly type 2 diabetes mellitus, arterialhypertension, central (visceral) obesity, dyslipidaemia observed asderanged lipoprotein levels typically characterised by elevated VLDL(very low density lipoproteins), small dense LDL particles and reducedHDL (high density lipoprotein) concentrations and reduced fibrinolysis.

Recent epidemiological research has documented that individuals withinsulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In type 2 diabetes mellitus atherosclerosis relatedconditions cause up to 80% of all deaths.

In clinical medicine there is awareness of the need to increase theinsulin sensitivity in patients with the metabolic syndrome and thus tocorrect the dyslipidaemia which is considered to cause the acceleratedprogress of atherosclerosis. However, currently this is not auniversally accepted diagnosis with well-defined pharmacotherapeuticindications.

The S-enantiomer of the compound of formula C below

2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid, is disclosed in PCT Publication Number WO99/62872. This compoundis reported to be a modulator of peroxisome proliferator-activatedreceptors (PPAR, for a review of the PPARs see T. M. Willson et al, JMed Chem 2000, Vol 43, 527) and has combined PPARα/PPARγ agonistactivity (Structure, 2001, Vol 9, 699, P. Cronet et al). This compoundis effective in treating conditions associated with insulin resistance.

Surprisingly a series of compounds has now been found which areselective PPARα modulators.

DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I

wherein R¹ represents chloro, fluoro or hydroxy as well as opticalisomers and racemates thereof as well as pharmaceutically acceptablesalts, prodrugs, solvates and crystalline forms thereof.

It will be appreciated by those skilled in the art the compounds offormula I contain an optically active centre and therefore can exist asenantiomers which can be separated as described later. It is expectedthat most, if not all, of the activity of the compounds of formula Iresides in one enantiomer: either the S or the R enantiomer or the (+)or the (−) enantiomer. The enantiomers which are more active in theassays which are described later are preferred forms of the presentinvention. It will be understood that the present invention includes allmixtures of this active enantiomer with the other enantiomer, forexample the racemic mixture, which is a useful intermediate for theactive enantiomer.

The active enantiomers may be isolated by separation of racemate forexample by fractional crystallization, resolution of HPLC on a chiralcolumn (for example a Chiralpak™ AD 250×50 column). Alternatively theactive enatiomers may be made by chiral synthesis from chiral startingmaterials under conditions which will not cause racemisation orepimerisation, or by derivatisation with a chiral reagent.

The term “prodrug ” as used in this specification includes derivativesof the carboxylic acid group which are converted in a mammal,particularly a human, into the carboxylic acid group or a salt orconjugate thereof. The term “prodrug ” also includes derivatives of theis hydroxy substituent (when R¹ represents hydroxy) which are convertedin a mammal, particularly a human, into the hydroxy group or a salt orconjugate thereof. It should be understood that, whilst not being boundby theory, it is believed that most of the activity associated with theprodrugs arises from the activity of the compound of formula I intowhich the prodrugs are converted. Prodrugs can be prepared by routinemethodology well within the capabilities of someone skilled in the art.Various prodrugs of carboxy and hydroxy are known in the art. Forexamples of such prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology. 42: 309–396, edited by K. Widder, et al.    (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and-   H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H.    Bundgaard p. 113–191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1–38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).

The above documents a to e are herein incorporated by reference.

In vivo cleavable esters are just one type of prodrug of the parentmolecule. An in vivo hydrolysable (or cleavable) ester of a compound ofthe formula (I) that contains a carboxy or a hydroxy group is, forexample, a pharmaceutically acceptable ester which is hydrolysed in thehuman or animal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethylesters, for example, methoxymethyl; C₁₋₆alkanoyloxymethyl esters, forexample, pivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example,1-cyclohexyl-carbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample, 5-methyl-1,3-dioxolen-2-onlymethyl; andC₁₋₆alkoxycarbonyloxyethyl esters, for example,1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in thecompounds of this invention. An in vivo hydrolysable (or cleavable)ester of a compound of the formula (I) that contains a hydroxy groupincludes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. Aselection of in vivo hydrolysable ester forming groups for hydroxyinclude alkanoyl, benzoyl, phenylacetyl and substituted benzoyl andphenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters),dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to givecarbamates), dialkylaminoacetyl and carboxyacetyl. Examples ofsubstituents on benzoyl include morpholino and piperazino linked from aring nitrogen atom via a methylene group to the 3- or 4- position of thebenzoyl ring.

The compounds of formula I have activity as medicaments, in particularthe compounds of formula I are selective agonists of PPARα, that is,their EC₅₀ for PPARα is at least ten times lower than their respectiveEC₅₀ for PPARγ wherein the EC₅₀s are measured and calculated asdescribed in the assays later in this document. The compounds of formulaI are potent and selective.

Specific compounds of the invention are:

-   2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid; preferably either the (R)-enantiomer or the (S)-enantiomer;-   2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid; preferably either the (R)-enantiomer or the (S)-enantiomer;-   2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid; preferably either the (R)-enantiomer or the (S)-enantiomer;-   (−)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid and-   (−)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;    and pharmaceutically acceptable salts, prodrugs, solvates and    crystalline forms thereof.

It will be understood by those skilled in the art that where (−) occursin the above list that the compound indicated has a negative rotationwhen measured using the conditions and concentration described in theexperimental section. It should be understood that salts of the parentacid are included even if a particular salt exhibits a (+) rotationprovided that the absolute configuration of the salt is the same as theconfiguration of the (−)-parent acid.

Specific enantiomers of the invention are selected from one or more ofthe following:

-   (R)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;-   (S)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;-   (R)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;-   (S)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;-   (R)-2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy    }ethyl)phenyl]propanoic acid;-   (S)-2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;-   (−)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid and-   (−)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic    acid;    and pharmaceutically acceptable salts, solvates and crystalline    forms thereof.

In the present specification the expression “pharmaceutically acceptablesalts” is intended to define but is not limited to base salts such asthe alkali metal salts, alkaline earth metal salts, ammonium salts,salts with basic amino acids, and salts with organic amines.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms. Certain compounds of the presentinvention may exist as tautomers. It is to be understood that thepresent invention encompasses all such tautomers.

Methods of Preparation

The compounds of the invention may be prepared as outlined below.However, the invention is not limited to these methods, the compoundsmay also be prepared as described for structurally related compounds inthe prior art. The reactions can be carried out according to standardprocedures or as described in the experimental section.

Compounds of formula I may be prepared by reacting a compound of formulaII

in which R¹ is as previously defined and R² represents a protectinggroup for carboxylic hydroxy group as described in the standard text“Protective Groups in Organic Synthesis”, 2^(nd) Edition (1991) byGreene and Wuts, with a de-protecting reagent. The protecting group mayalso be a resin, such as Wang resin or 2-chlorotrityl chloride resin.Protecting groups may be removed in accordance to techniques which arewell known to those skilled in the art. One such protecting group iswhere R² represents C₁₋₆alkoxy group or an arylalkoxy group egbenzyloxy, such that COR² represents an ester. Such esters can bereacted with a a de-protecting reagent e.g. a hydrolysing agent, forexample lithium hydroxide in a mixture of THF and water, at atemperature in the range of 0–100° C. to give compounds of formula I.

Compounds of formula II may be prepared by reacting a compound offormula III

in which R² is as previously defined and X is a leaving group forexample halo e.g. chloro with a compound of formula IV

in which R¹ is as previously defined or a protected hydroxy group forexample R¹ is benzyloxy.

Compounds of formula III and IV may be prepared by methods described inthe Examples or by analogous methods known to those skilled in the art.

Compounds of formula II, III and IV are believed to be novel and areclaimed herein as useful intermediates in the preparation of compoundsof formula I.

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

The expression “inert solvent” refers to a solvent which does not reactwith the starting materials, reagents, intermediates or products in amanner which adversely affects the yield of the desired product.

Pharmaceutical Preparations

The compounds of the invention will normally be administered via theoral, parenteral, intravenous, intramuscular, subcutaneous or in otherinjectable ways, buccal, rectal, vaginal, transdermal and/or nasal routeand/or via inhalation, in the form of pharmaceutical preparationscomprising the active ingredient either as a free acid, or apharmaceutical acceptable organic or inorganic base addition salt, in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated and the route of administration, the compositionsmay be administered at varying doses.

Suitable daily doses of the compounds of the invention in therapeuticaltreatment of humans are about 0.0001–100 mg/kg body weight, preferably0.001–10 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules whichmay be formulated by methods known to those skilled in the art toprovide doses of the active compound in the range of 0.5 mg to 500 mgfor example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including any of the compounds of theinvention, or pharmaceutically acceptable derivatives thereof, inadmixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

Pharmacological Properties

The present compounds of formula (I) are useful for the prophylaxisand/or treatment of clinical conditions associated with inherent orinduced reduced sensitivity to insulin (insulin resistance) andassociated metabolic disorders (also known as metabolic syndrome). Theseclinical conditions will include, but will not be limited to, generalobesity, abdominal obesity, arterial hypertension, hyperinsulinaemia,hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristicallyappearing with insulin resistance. This dyslipidaemia, also known as theatherogenic lipoprotein profile, is characterised by moderately elevatednon-esterified fatty acids, elevated very low density lipoprotein (VLDL)triglyceride rich particles, high Apo B levels, low high densitylipoprotein (HDL) levels associated with low apoAI particle levels andhigh Apo B levels in the presence of small, dense, low densitylipoproteins (LDL) particles, phenotype B.

The compounds of the present invention are expected to be useful intreating patients with combined or mixed hyperlipidemias or variousdegrees of hypertriglyceridemias and postprandial dyslipidemia with orwithout other manifestations of the metabolic syndrome.

Treatment with the present compounds is expected to lower thecardiovascular morbidity and mortality associated with atherosclerosisdue to their antidyslipidaemic as well as antiinflammatory properties.The cardiovascular disease conditions include macro-angiopathies ofvarious internal organs causing myocardial infarction, congestive heartfailure, cerebrovascular disease and peripheral arterial insufficiencyof the lower extremities. Because of their insulin sensitizing effectthe compounds of formula I are also expected to prevent or delay thedevelopment of type 2 diabetes from the metabolic syndrome and diabetesof pregnancy. Therefore the development of long-term complicationsassociated with chronic hyperglycaemia in diabetes mellitus such as themicro-angiopathies causing renal disease, retinal damage and peripheralvascular disease of the lower limbs are expected to be delayed.Furthermore the compounds may be useful in treatment of variousconditions outside the cardiovascular system whether or not associatedwith insulin resistance, like polycystic ovarian syndrome, obesity,cancer and states of inflammatory disease including neurodegenerativedisorders such as mild cognitive impairment, Alzheimer's disease,Parkinson's disease and multiple sclerosis.

The compounds of the present invention are expected to be useful incontrolling glucose levels in patients suffering from type 2 diabetes.

The present invention provides a method of treating or preventingdyslipidemias, the insulin resistance syndrome and/or metabolicdisorders (as defined above) comprising the administration of a compoundof formula I to a mammal (particularly a human) in need thereof.

The present invention provides a method of treating or preventing type 2diabetes comprising the administration of an effective amount of acompound of formula I to a mammal (particularly a human) in needthereof.

In a further aspect the present invention provides the use of a compoundof formula I as a medicament.

Treatment with the present compounds is expected to lower thecardiovascular morbidity and mortality associated with atherosclerosisdue to their antidyslipidaemic as well as antiinflammatory properties.The cardiovascular disease conditions include macro-angiopathies ofvarious internal organs causing myocardial infarction, congestive heartfailure, cerebrovascular disease and peripheral arterial insufficiencyof the lower extremities. Because of their insulin sensitizing effectthe compounds of formula I are also expected to prevent or delay thedevelopment of type 2 diabetes from the metabolic syndrome and diabetesof pregnancy. Therefore the development of long-term complicationsassociated with chronic hyperglycaemia in diabetes mellitus such as themicro-angiopathies causing renal disease, retinal damage and peripheralvascular disease of the lower limbs are expected to be delayed.Furthermore the compounds may be useful in treatment of variousconditions outside the cardiovascular system whether or not associatedwith insulin resistance, like polycystic ovarian syndrome, obesity,cancer and states of inflammatory disease including neurodegenerativedisorders such as mild cognitive impairment, Alzheimer's disease,Parkinson's disease and multiple sclerosis.

The compounds of the present invention are expected to be useful incontrolling glucose levels in patients suffering from type 2 diabetes.

The present invention provides a method of treating or preventingdyslipidemias, the insulin resistance syndrome and/or metabolicdisorders (as defined above) comprising the administration of a compoundof formula I to a mammal (particularly a human) in need thereof.

The present invention provides a method of treating or preventing type 2diabetes comprising the administration of an effective amount of acompound of formula I to a mammal (particularly a human) in needthereof.

In a further aspect the present invention provides the use of a compoundof formula I as a medicament.

In a further aspect the present invention provides the use of a compoundof formula I in the manufacture of a medicament for the treatment ofinsulin resistance and/or metabolic disorders.

Combination Therapy

The compounds of the invention may be combined with other therapeuticagents that are useful in the treatment of disorders associated with thedevelopment and progress of atherosclerosis such as hypertension,hyperlipidaemias, dyslipidaemias, diabetes and obesity. The compounds ofthe invention may be combined with another therapeutic agent thatdecreases the ratio of LDL:HDL or an agent that causes a decrease incirculating levels of LDL-cholesterol. In patients with diabetesmellitus the compounds of the invention may also be combined withtherapeutic agents used to treat complications related tomicro-angiopathies.

The compounds of the invention may be used alongside other therapies forthe treatment of metabolic syndrome or type 2 diabetes and itsassociated complications, these include biguanide drugs, for examplemetformin, phenformin and buformin, insulin (synthetic insulinanalogues, amylin) and oral antihyperglycemics (these are divided intoprandial glucose regulators and alpha-glucosidase inhibitors). Anexample of an alpha-glucosidase inhibitor is acarbose or voglibose ormiglitol. An example of a prandial glucose regulator is repaglinide ornateglinide.

In another aspect of the invention, the compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with another PPARmodulating agent. PPAR modulating agents include but are not limited toa PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts,solvates, solvates of such salts or prodrugs thereof. Suitable PPARalpha and/or gamma agonists, pharmaceutically acceptable salts,solvates, solvates of such salts or prodrugs thereof are well known inthe art. These include the compounds described in WO 01/12187, WO01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on TherapeuticPatents, 10 (5), 623–634 (in particular the compounds described in thepatent applications listed on page 634) and J Med Chem, 2000, 43, 527which are all incorporated herein by reference. Particularly a PPARalpha and/or gamma agonist refers to NN622/Ragaglitazar, BMS 298585,WY-14643, clofibrate, fenofibrate, bezafibrate, gemfibrozil andciprofibrate; GW 9578, ciglitazone, troglitazone, pioglitazone,rosiglitazone, eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.Particularly a PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy)-phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

In addition the combination of the invention may be used in conjunctionwith a sulfonylurea for example: glimepiride, glibenclamide (glyburide),gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide,acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid,glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide,phenbutamide, tolcylamide and tolazamide. Preferably the sulfonylurea isglimepiride or glibenclamide (glyburide). More preferably thesulfonylurea is glimepiride. Therefore the present invention includesadministration of a compound of the present invention in conjunctionwith one, two or more existing therapies described in this paragraph.The doses of the other existing therapies for the treatment of type 2diabetes and its associated complications will be those known in the artand approved for use by regulatory bodies for example the FDA and may befound in the Orange Book published by the FDA. Alternatively smallerdoses may be used as a result of the benefits derived from thecombination.

The present invention also includes a compound of the present inventionin combination with a cholesterol-lowering agent. Thecholesterol-lowering agents referred to in this application include butare not limited to inhibitors of HMG-CoA reductase(3-hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoAreductase inhibitor is a statin selected from the group consisting ofatorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin,itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatinand simvastatin, or a pharmaceutically acceptable salt, especiallysodium or calcium, or a solvate thereof, or a solvate of such a salt. Aparticular statin is atorvastatin, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. A moreparticular statin is atorvastatin calcium salt. A particularly preferredstatin is, however, a compound with the chemical name(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, [also known as(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] or a pharmaceutically acceptable salt or solvate thereof, or asolvate of such a salt. The compound(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, and its calcium and sodium salts are disclosed in European PatentApplication, Publication No. EP-A-0521471, and in Bioorganic andMedicinal Chemistry, (1997), 5(2), 437–444. This latter statin is nowknown under its generic name rosuvastatin.

In the present application, the term “cholesterol-lowering agent” alsoincludes chemical modifications of the HMG-CoA reductase inhibitors,such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present inventionin combination with an inhibitor of the ileal bile acid transport system(13AT inhibitor).

Suitable compounds possessing 1BAT inhibitory activity have beendescribed, see for instance the compounds described in WO 93/16055, WO94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/50051, EP 864582, EP489423, EP549967, EP573848, EP624593, EP624594, EP624595 andEP624596 and the contents of these patent applications are incorporatedherein by reference.

Particular classes of IBAT inhibitors suitable for use in the presentinvention are benzothiepines, and the compounds described in the claims,particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 areincorporated herein by reference. Other suitable classes of IBATinhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and1,5-benzothiazepines. A further suitable class of IBAT inhibitors is the1,2,5-benzothiadiazepines.

One particular suitable compound possessing MBAT inhibitory activity is(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ylβ-D-glucopyranosiduronicacid (EP 864 582). Other suitable IBAT inhibitors include one of:

-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{(N-[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzy}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl    }-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    and-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4)-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula I, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

a CETP (cholesteryl ester transfer protein) inhibitor, for example thosereferenced and described in WO 00/38725 page 7 line 22-page 10, line 17which are incorporated herein by reference;

a cholesterol absorption antagonist for example azetidinones such as SCH58235 and those described in U.S. Pat. No. 5,767,115 which areincorporated herein by reference;

a MTP (microsomal transfer protein) inhibitor for example thosedescribed in Science, 282, 751–54, 1998 which are incorporated herein byreference;

a nicotinic acid derivative, including slow release and combinationproducts, for example, nicotinic acid (niacin), acipimox and niceritrol;

a phytosterol compound for example stanols; probucol;

an anti-obesity compound for example orlistat (EP 129,748) andsibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);

an antihypertensive compound for example an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin II receptor antagonist, anandrenergic blocker, an alpha andrenergic blocker, a beta andrenergicblocker, a mixed alpha/beta andrenergic blocker, an andrenergicstimulant, calcium channel blocker, an AT-1 blocker, a saluretic, adiuretic or a vasodilator;

a CB1 antagonist or inverse agonist for example as described inWO01/70700 and EP 65635;

a Melanin concentrating hormone (MCH) antagonist;

a PDK inhibitor; or

modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formulaI include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula I include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

Therefore in an additional feature of the invention, there is provided amethod for for the treatment of type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of formula I, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof insimultaneous, sequential or separate administration with an effectiveamount of one the other compounds described in this combination section,or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of one the other compounds described in thiscombination section or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula I, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and one of the other compounds described in thiscombination section or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula I, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and one of the other compounds described in this combination section ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula I, or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) one of the other compounds described in this combination section    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula I, or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) one of the other compounds described in this combination section    or a pharmaceutically acceptable salt, solvate, solvate of such a    salt or a prodrug thereof, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to another feature of the invention there is provided the useof a compound of the formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and one of theother compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in the manufacture of a medicament for use in the thetreatment of metabolic syndrome or type 2 diabetes and its associatedcomplications in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula I, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and one of theother compounds described in this combination section, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in the manufacture of a medicament for use in thetreatment of hyperlipidaemic conditions in a warm-blooded animal, suchas man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, optionallytogether with a pharmaceutically acceptable diluent or carrier, with thesimultaneous, sequential or separate administration of an effectiveamount of one of the other compounds described in this combinationsection, or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

EXAMPLES

¹H NMR and ¹³C NMR measurements were performed on a Varian Mercury 300or Varian UNITY plus 400, 500 or 600 spectrometers, operating at ¹Hfrequencies of 300, 400, 500 and 600 MHz, respectively, and at ¹³Cfrequencies of 75, 100, 125 and 150 MHz, respectively. Measurements weremade on the delta scale (δ).

Unless otherwise stated, chemical shifts are given in ppm with thesolvent as internal standard.

Abbreviations DMSO dimethyl sulfoxide EtOAc ethyl acetate DMFN,N-dimethylformamide THF tetrahydrofuran MeCN acetonitrile MeOHmethanol TFA trifluoroacetic acid NH₄OAc ammonium acetate t triplet ssinglet d doublet q quartet m multiplet bs broad singlet

Example 12-{[2-(4-Chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoicacid (i) [2-(4-Chlorophenyl)ethyl]ethanethioate

1-(2-Chloroethyl)-4-chlorobenzene (0.700 g, 4.00 mmol), thioacetic acid(0.320 g, 4.20 mmol) and triethylamine (0,425 g, 4.20 mmol) weredissolved in MeOH (8 ml). The solution was warmed with microwaves for900 seconds at 150° C. The mixture was used in the next step withoutpurification.

(ii)2-{[2-(4-Chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoicacid

The reaction vessel was flushed with argon. To a part 0.8 ml (0.400mmol) of the mixture from the reaction step above was added understirring sodium methanethiolate (56.5 mg, is 0.800 mmol) in MeOH (0.2ml). After an hour methyl2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate(0.200 g, 0.484 mmol, prepared as described in Example 2) inacetonitrile (0.800 ml) was added. The mixture was stirred for 16 hunder an argon atmosphere and then centrifuged under vacuum at 35° C. 2ml 0.5 M LiOH solution (THF/water 7:1) was added and the mixture wasstirred vigorously for 20 h. After acidification with 12 M HCl (100 μl)the stirring was continued for another hour. The crude product wasfiltered through a Teflon™ filter and further purified using preparativeBPLC (0.2% TFA/MeCN, gradient). The pooled fractions were centrifugedunder vacuum giving 18 mg of the desired product (yield 7%).

¹H-NMR (400 MHz, CDCl₃): 2.75–2.95 (m, 5H), 3.06 (t, 2H), 3.10 (s, 3H),3.16 (dd, 1H), 3.45 (dd, 1H), 4.14 (d, 2H), 6.87 (d, 2H), 7.05 (d, 2H),7.11–7.27 (m, 8H).

(iii) (−)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoic acid

The (−)-enantiomer of2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)-oxy]phenoxy}ethyl)phenyl]propanoicacid was separated from the racemate by chiral chromatography. AChiralpak AD JF003 (250×20 mm i.d.) column was used and ethanol/formicacid 100/0.1% as mobile phase. The racemate (2 g) was dissolved inethanol (20 mg/ml) and was injected onto the column. The first elutingpeak was collected and UV-detected. The product (0.9 g) was obtainedwith an enantiomeric purity=99.2%. The optical rotation was found to be[α]²⁰ _(D)=−29° by dissolving the enantiomer in ethanol to give aconcentration of 0.5 g/100 ml. The optical rotation was measured at 20°C. using the sodium line at 589 nm.

¹H NMR (500 MHz, CD₃OD): 7.18–7.25 (6H, m), 7.15 (2H, d), 7.13 (2H, d),4.16 (2H, t), 3.45 (1H, t), 3.14 (3H, s), 3.11 (1H, m), 3.04(2H, t),2.77–2.90 (5H, m).

Example 22-{[2-(4-Hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoicacid (i) Methyl 2-chloro-3-[4-(2-hydroxyethyl)phenyl]propanoate

2-(4-Aminophenyl)ethanol (11 g, 81 mmol) and 32 ml conc HCl wasdissolved in acetone and cooled to 0° C. Sodium nitrite (5.6 g, 81 mmol)in 20 ml water was added dropwise. The temperature was kept under 0° C.After one hour, methyl acrylate (70 g, 808 mmol) and CuI (1.6 g, 8 mmol)were added (<0° C.). The reaction mixture was stirred at roomtemperature overnight.

The solvent was evaporated and water was added. The water phase wasextracted three times with EtOAc, the organic phases were pooled andwashed with water, dried (MgSO₄) and evaporated under reduced pressure.The crude product was purified by flash chromatography using a 65:35mixture of EtOAc and heptane as eluent. Further purification bypreparative HPLC (using a gradient of CH₃CN/5% CH₃CN-waterphasecontaining 0.1M NH₄OAc as eluent) gave 9.7 g product (yield 49%) as anoil.

¹HNMR (400 MHz, CDCl₃): 2.84 (t, 3H), 3.15 (dd, 1H), 3.35 (dd, 1H), 3.75(s, 3H), 3.84 (t, 3H), 4.43 (t, 1H), 7.17 (d, 4H)

(ii) Methyl3-(4-{2-[4-(benzyloxy)phenoxy]ethyl}phenyl)-2-chloropropanoate

Triphenylphosphine (2.4 g, 9 mmol) was added to a solution of methyl2-chloro-3-[4-(2-hydroxyethyl)phenyl]propanoate (2.1 g, 8.5 mmol) and4-(benzyloxy)phenol (1.7 g, 8 mmol) in 20 ml toluene under nitrogenatmosphere. The solution was warmed to 55° C. and diisopropylazodicarboxylate (1.8 g, 9 mmol) was added. The reaction mixture wasstirred at 55° C. overnight.

The mixture was allowed to cool and the solvent was evaporated underreduced pressure. The crude product was purified by flash chromatographyusing a 80:20 mixture of heptane and EtOAc as eluent to yield 2.28 g ofthe desired product (yield 61%) as colourless crystals.

¹HNMR (400 MHz, CDCl₃): 3.05 (t, 2H), 3.16 (dd, 1H), 3.36 (dd, 1H), 3.75(s, 3H), 4.12 (t, 2H), 4.45 (t, 1H), 5.01 (s, 2H), 6.82 (m, 2H), 6.90(m, 2H), 7.13–7.27 (m, 4H), 7.29–7.47 (m, 5H).

(iii) Methyl 2-chloro-3-{4-[2-(4-hydroxyphenoxy)ethyl]phenyl}propanoate

Methyl 3-(4-{2-[4-(benzyloxy)phenoxy]ethyl}phenyl)-2-chloropropanoate(1.0 g, 2.4 mmol) and dimethyl sulfide (0.9 g, 14 mmol) was dissolved in60 ml CH₂Cl₂. Boron trifluoride etherate (2.0 g, 14 mmol) was addeddroppwise to the stirred solution. The reaction mixture was stirred fortwo days at room temperature. Another equivalent (0.4 g, 2.87 mmol)boron trifluoride etherate was added and the stirring was continuedovernight. Water was added. The phases were separated and the aqueousphase was extracted twice with CH₂Cl₂. The organic phases were pooled,washed (water, brine), dried (Na₂SO₄) and evaporated under reducedpressure. Further purification by preparative HPLC using a gradient ofCH₃CN/5% CH₃CN-waterphase containing 0.1M NH₄OAc gave 0.55 g of thedesired product (yield 52%) as an oil.

¹HNMR (400 M&, CDCl₃): 3.04 (t, 2H), 3.16 (dd, 1H), 3.35 (dd, 1H), 3.75(s, 3H), 4.10 (t, 2H), 4.40 (t, 1H), 6.75 (m, 4H), 7.12–7.29 (m, 4H).

(iv) Methyl2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate

Methyl 2-chloro-3-{4-[2-(4-hydroxyphenoxy)ethyl]phenyl}propanoate (334mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) was dissolved in 20ml dichlormethane and cooled to −20° C. under nitrogen atmosphere.Methanesulfonyl chloride (114 mg, 1.0 mmol) was added dropwise. Themixture was allowed to reach room temperature. After 2 hoursdichlormethane was added, the mixture was washed (water, brine), dried(Na₂SO₄) and evaporated under reduced pressure to yield 394 mg pureproduct (yield 96%).

¹HNMR (400 MHz, CDCl₃): 3.02–3.11 (m, 5H), 3.15 (dd, 1H), 3.35 (dd, 1H),3.74 (s, 3H), 4.14 (t, 2H), 4.44 (t, 1H), 5.29 (s, 2H), 6.88 (d, 2H),7.14–7.25 (m, 6H).

(v) Methyl2-({2-[4-(benzyloxy)phenyl]ethyl}thio)-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate

2-[4-(Benzyloxy)phenyl]ethanethiol (334 mg, 1.4 mmol), methyl2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate(394 mg, 0.95 mmol) and potassium carbonate (189 mg, 1.4 mmol) weredissolved in 14 ml dry DMF. and stirred under nitrogen atmosphere atroom temperature overnight.

The solvent was evaporated under reduced pressure and the residue wasdissolved in toluene. The organic phase was washed (water, brine), dried(MgSO₄) and evaporated. Further purification by preparative HPLC using agradient of CH₃CN/5% CH₃CN-waterphase containing 0.1M NH₄OAc gave 477 mgof the desired product (yield 75%).

¹HNMR (400 MHz, CDCl₃): 2.76–2.89 (m, 4H), 2.95 (dd, 1H), 3.09 (m, 5H),3.20 (dd, 1H), 3.53 (m, 1H), 3.70 (s, 3H), 4.15 (t, 2H), 5.06 (s, 2H),6.91 (m, 4H), 7.07–7.24 (m, 8H), 7.31–7.48 (m, 5H).

(vi) Methyl 2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate

To a solution of methyl2-({2-[4-(benzyloxy)phenyl]ethyl}thio)-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate(477 mg, 0.8 mmol) and 15 ml dichlormethane, dimethyl sulfide (239 mg,3.8 mol) and boron trifluoride etherate (545 mg, 3.8 mmol) were added.After 18 hours of stirring water was added to the reaction. The phaseswere separated and the aqueous phase was extracted twice withdichlormethane. The organic phases were pooled, dried (MgSO₄) andevaporated under reduced pressure. 274 mg of the desired product (yield67%) was obtained as an oil.

¹HNMR (400 MHz, CDCl₃): 2.70–2.85 (m, 4H), 2.91 (dd, 1H), 3.05 (t, 2H),3.10 (s, 3H), 3.17 (dd, 1H), 3.49 (m, 1H), 3.68 (s, 3H), 4.13 (t, 2H),6.72 (d, 2H), 6.87 (d, 2H), 6.99 (d, 2H), 7.10–7.22 (m, 6H)

(vii)2-{[2-(4-Hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid

Methyl2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenyl]propanoate(105 mg, 0.2 mmol) was dissolved in 6.5 ml of a 7:1 mixture of THF andwater and cooled on an ice-bath. Lithium hydroxide (9.4 mg, 0.4 mmol)was added. Water was added to the reaction mixture after 24 hours ofstirring at room temperature. The THF was evaporated under reducedpressure and the residue was acidified with 1M hydrochloric acid. Thewater phase was extracted with EtOAc (×3), the organic phases werepooled, washed (water, brine), dried (MgSO₄) and evaporated. The crudeproduct was purified using preparative HPLC (eluent: CH₃CN/5%CH₃CN-waterphase containing 0.1M NH₄OAc) to give 74 mg of the desiredproduct (yield 97%) as an oil.

¹HNMR (400 MHz, CDCl₃): 2.68–2.95 (m, 5H), 3.05 (t, 2H), 3.10 (s, 3H),3.17 (dd, 1H), 3.47 (m, 1H), 4.12 (t, 2H), 6.70 (d, 2H), 6.86 (d, 2H),6.97 (d, 2H), 7.12–7.21 (m, 6H).

¹³CNMR (100 MHz, CDCl₃): 33.8, 35.1, 35.5, 37.2, 37.3, 48.1, 69.3,115.6, 115.8, 123.3, 129.3, 129.4, 129.9, 132.3, 136.2, 136.9, 142.8,154.4, 158.0, 177.2.

(viii)(−)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoicacid

The racemate of2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)-oxy]phenoxy}ethyl)phenyl]propanoicacid was separated into its enantiomers using chiral chromatography. AChiralpak AD JDB01+AS003 (336×100 mm i.d.) and ethanol/formic acid100/0.01% was used as mobile phase. The racemate (9 g) was dissolved inethanol and injected onto the column. The first eluting peak wascollected and UV-detected. The product (4.1 g) was obtained with anenantiomeric purity>99%. The optical rotation was found to be [α]²⁰_(D)=−33° by dissolving the enantiomer in methanol to give aconcentration of 0.64 g/100 ml. The optical rotation was measured at 20°C. using the sodium line at 589 nm.

¹H NMR (500 MHz, CD₃OD): 7.17–7.22 (6H, m), 6.99 (2H, d), 6.94 (2H, d),6.69 (2H, d), 4.17 (2H, t), 3.46 (1H, t), 3.16 (3H, s), 3.13 (1H, dd),3.05 (2H, t), 2.69–2.88 (5H, m).

Example 32-{[2-(4-Fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenyl]propanoicacid (i) [2-(4-fluorophenyl)ethyl]ethanethioate

To a solution of DMF (60 ml) and thioacetic acid (2.1 g, 28 mmol),cooled in an ice-bath, was added cesium carbonate (9.1 g, 28 mmol). Thereaction mixture immediately turned orange.1-(2-Chloroethyl)-4-fluorobenzene (4 g, 25 mmol) was added, the ice-bathwas removed and the reaction was stirred overnight. The solvent wasevaporated and the residue was dissolved in EtOAc. The organic phase waswashed (water), dried (NaSO₄) and evaporated under reduced pressure toyield 5 g (99%) of the desired product as an oil.

¹HNMR (400 MHz, CDCl₃): 2.33 (s, 3H), 2.83 (t, 2H), 3.09 (t, 2H), 6.98(t, 2H), 7.17 (m, 2H).

¹³CNMR (100 MHz, CDCl₃): 30.8, 30.9, 35.3, 115.4, 115.6, 130.2, 130.3,135.9, 160.7, 195.8.

(ii) Methyl2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenyl]propanoate

[2-(4-Fluorophenyl)ethyl]ethanethioate (96 mg, 0.48 mmol) was dissolvedin 1 ml methanol under nitrogen atmosphere. To this slurry was addedsodium methanethiolate (33.9 mg, 0.48 mmol). After 30 minutes ofstirring methyl2-chloro-3-[4-(2-{4-[(methylsulfonyl)-oxy]phenoxy}ethyl)phenyl]propanoate(200 mg, 0.48 mmol) dissolved in 2 ml CH₃CN was added. The resultingmixture was stirred overnight.

The solvent was evaporated and the residue was dissolved in EtOAc. Theorganic phase was washed (water), dried (MgSO₄) and evaporated underreduced pressure.

Further purification by preparative HPLC (using a gradient ofCH₃CN/5%CH₃CN-waterphase containing 0.1M NH₄OAc) gave 82 mg of thedesired product (yield 32%).

¹HNMR (500 MHz, CDCl₃): 2.82–3.00 (m, 5H), 3.10 (t, 2H), 3.14 (s, 3H),3.22 (dd, 1H), 3.53 (m, 1H), 3.72 (s, 3H), 4.18 (t, 2H), 6.92 (d, 2H),7.0 (t, 2H), 7.15 (m, 4H), 7.23 (m, 4H).

(iii)2-{[2-(4-Fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid

Methyl2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoate(77 mg, 0.14 mmol) was dissolved in 2.5 ml of a 4:1 mixture of THF andwater and cooled on an ice-bath. Lithium hydroxide (6.9 mg, 0.29 mmol)was added. Water was added after 2 days of stirring at room temperature.The THF was evaporated under reduced pressure. The aqueous phase wasacidified with 1M HCl and extracted with EtOAc three times. The organicphases were pooled, washed (water, brine), dried (MgSO₄) and evaporated.The crude product was purified using preparative HPLC (eluent: CH₃CN/5%CH₃CN-waterphase containing 0.1M NH₄Oac). 24 mg of the desired product(yield 30%) was obtained as an oil.

¹HNMR (500 MHz, CDCl₃): 2.82–3.00 (m, 5H), 3.10 (t, 2H), 3.14 (s, 3H),3.21 (dd, 1H), 3.52 (m, 1H), 4.18 (t, 2H), 6.90 (d, 2H), 6.99 (t, 2H),7.13 (m, 2H), 7.16–7.26 (m, 6H).

Biological Activity

Formulations

Compounds were dissolved in DMSO to obtain 16 mM stock solutions. Beforeassays, stock solutions were further diluted in DMSO and culture media.

General Chemicals and Reagents

Luciferase assay reagent was purchased from Packard, USA. RestrictionEnzymes were from Boehringer and Vent polymerase from New EnglandBiolabs.

Cell Lines and Cell Culture Conditions

U2-OS, (Osteogenic sarcoma, Human) was purchased from ATCC, USA. Cellswere expanded and refrozen in batches from passage number six. Cellswere cultured in Dulbecco's modified Eagle medium (DMEM) with 25 mMglucose, 2 mM glutamine or 4 mM L-alanyl-L-glutamine, 10% fetal calfserum, at 5% CO₂. Phosphate buffered saline (PBS) without addition ofcalcium or magnesium was used. All cell culture reagents were from Gibco(USA) and 96-well cell culture plates were purchased from Wallach.

Plasmid Constructs for Heterologous Expression

Standard recombinant DNA techniques were carried out as described byAusubel (7). The Luciferase reporter vector, pGL5UAS (clone consists offive copies of the GAL4 DNA binding sequence,5′-CGACGGAGTACTGTCCTCCGAGCT-3′, cloned into the SacI/XhoI sites ofpGL3-Promoter (Promega). The SacI/XhoI fragment carrying the UAS siteswas constructed using annealed overlapping oligonucleotides.

Expression vectors used are based upon pSG5 (Stratagene). All vectorscontain an EcoRI/NheI fragment encoding the DNA binding domain of GAL4(encoding amino acid positions 1–145 of database accession numberP04386) followed by an in-frame fusion to a fragment encoding thenuclear localisation sequence from T antigen of Polyoma Virus. Thenuclear localisation sequence was constructed using annealed overlappingoligonucleotides creating NheI/KpnI sticky ends(5′-CTAGCGCTCCTAGAAGAAACGCAAGGTTGGTAC-3′). The ligand binding domainsfrom human and mouse PPARα and human and mouse PPARγ were PCR amplifiedas KpnI/BamHI fragments and cloned in frame to the GAL4 DNA bindingdomain and the nuclear localisation sequence. The sequence of allplasmid constructs used were confirmed by sequencing.

The following expression vectors were used for transient transfections:

vector encoded PPAR subtype sequence reference¹ pSGGALhPPa human PPARαS74349, nt 625–1530 pSGGALmPPa murine PPARα X57638, nt 668–1573pSGGALhPPg human PPARγ U63415, nt 613–1518 pSGGALmPPg murine PPARγU09138, nt 652–1577 ¹refers to nucleotide positions of data base entryused to express the ligand binding domain.Transient Transfections

Frozen stocks of cells from passage number six were thawed and expandedto passage number eight before transfections. Confluent cells weretrypsinised, washed and pelleted by centrifugation at 270×g for 2minutes. The cell pellet was resuspended in cold PBS to a cellconcentration of about 18×10⁶ cells/ml. After addition of DNA, the cellsuspension was incubated on ice for approximately 5 minutes beforeelectroporation at 230 V, 960 μF in Biorad's Gene Pulser™ in 0.5 mlbatches. A total of 50 μg DNA was added to each batch of 0.5 ml cells,including 2.5 μg expression vector, 25 μg reporter vector and 22.5 μgunspecific DNA (pBluescript, Stratagene).

After electroporation, cells were diluted to a concentration of 320′000cells/ml in DMEM without phenol red, and approximately 25′000 cells/wellwere seeded in 96-well plates. In order to allow cells to recover,seeded plates were incubated at 37° C. for 34 hours before addition oftest compounds. In assays for PPARα, the cell medium was supplementedwith resin-charcoal stripped fetal calf serum (FCS) in order to avoidbackground activation by fatty acid components of the FCS. Theresin-charcoal stripped FCS was produced as follows; for 500 ml ofheat-inactivated FCS, 10 g charcoal and 25 g Bio-Rad Analytical GradeAnion Exchange Resin 200–400 mesh were added, and the solution was kepton a magnetic stirrer at room temperature over night. The following day,the FCS was centrifuged and the stripping procedure was repeated for 4–6hours. After the second treatment, the FCS was centrifuged and filtersterilised in order to remove remnants of charcoal and resin.

Assay Procedure

Stock solutions of compounds in DMSO were diluted in appropriateconcentration ranges in master plates. From master plates, compoundswere diluted in culture media to obtain test compound solutions forfinal doses.

After adjustment of the amount of cell medium to 75 μl in each well, 50μl test compound solution was added. Transiently transfected cells wereexposed to compounds for about 24 hours before the luciferase detectionassay was performed. For luciferase assays, 100 μl of assay reagent wasadded manually to each well and plates were left for approximately 20minutes in order to allow lysis of the cells. After lysis, luciferaseactivity was measured in a 1420 Multiwell counter, Victor, from Wallach.

Reference Compounds

The IZD pioglitazone was used as reference substance for activation ofboth human and murine PPARγ. 5,8,11,14-Eicosatetrayonic acid (ETYA) wasused as reference substance for human PPARα.

Calculations and Analysis

For calculation of EC₅₀ values, a concentration-effect curve wasestablished. Values used were derived from the average of two or threeindependent measurements (after subtraction of the background averagevalue) and were expressed as the percentage of the maximal activationobtained by the reference compound. Values were plotted against thelogarithm of the test compound concentration. EC₅₀ values were estimatedby linear intercalation between the data points and calculating theconcentration required to achieve 50% of the maximal activation obtainedby the reference compound.

The compounds of formula I have an EC₅₀ of less than 5 μmol/l for PPARAand particular compounds have an EC₅₀ of less than 1.0 μmol/l.Additionally in particular compounds the ratio of the EC₅₀ (PPARγ): EC₅₀(PPARα) is greater than 25:1. It is believed that this ratio isimportant with respect to the pharmacological activity of the compoundsand to their therapeutic profile.

In addition the compounds of the present invention exhibit improved DMPK(Drug Metabolism and Pharmacokinetic) properties for example theyexhibit improved metabolic stability in vitro. The compounds also have apromising toxicological profile.

1. A compound of formula I

wherein R¹ represents chloro, fluoro or hydroxy as well as opticalisomers and racemates thereof as well as pharmaceutically acceptablesalts, prodrugs, solvates and crystalline forms thereof.
 2. A compoundselected from2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid;2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid; and2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid; and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof.
 3. The compound(−)-2-{[2-(4-chlorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid.
 4. The compound(−)-2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid.
 5. The (R)-enantiomer or the (S)-enantiomer of2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoicacid.
 6. A pharmaceutical formulation comprising a compound according toany one of claim 1 to 5 in admixture with pharmaceutically acceptableadjuvants, dilutents and/or carriers.
 7. A method of treatingdyslipidemia comprising the administration of a compound according toany one of claim 1–5 to a mammal in need thereof.
 8. A method oftreating type 2 diabetes comprising the administration of an effectiveamount of a compound of formula I according to any one of claim 1–5 to amammal in need thereof.
 9. A process for preparing a compound of formulaI as defined in claim 1 comprising reacting a compound of formula II

in which R¹ is as defined in claim 1 and R² represents a protectinggroup for a carboxylic hydroxy group with a de-protecting reagent.
 10. Acompound of formula II

wherein R¹ represents chloro, fluoro or hydroxy and R² represents aprotecting group for a carboxylic hydroxy group.
 11. A compound offormula III

in which R² represents a protecting group for a carboxylic hydroxy groupand X is a leaving group.
 12. A pharmaceutical composition comprising acompound as claimed in any one of claims 1 to 5 combined with anotherPPAR modulating agent.
 13. A pharmaceutical composition comprising acompound as claimed in any one of claims 1 to 5 combined with acholesterol-lowering agent.
 14. A pharmaceutical composition comprisinga compound as claimed in any one of claims 1 to 5 combined with aHMG-CoA reductase inhibitor.
 15. A pharmaceutical composition comprisinga compound as claimed in any one of claims 1 to 5 combined withatorvastatin or a pharmaceutically acceptable salt, solvate, crystallineform or prodrug thereof.
 16. A pharmaceutical composition comprising acompound as claimed in any one of claims 1 to 5 combined withrosuvastatin or a pharmaceutically acceptable salt thereof.
 17. Apharmaceutical composition comprising a compound as claimed in any oneof claims 1 to 5 combined with an IBAT inhibitor.
 18. A pharmaceuticalcomposition according to claim 17 wherein the IBAT inhibitor is selectedfrom one of:1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;and1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.